Heparin-induced thrombocytopenia with thrombosis

Arnold R, Kim R, Zhou Y, Tang B. Budgetary impact of heparin-induced thrombocytopenia with thrombosis and treatment with the direct thrombin inhibitor Argatroban (P401E). ASHP 39th Midyear Clinical Meeting. Orlando, FL, 2004. 

Latham P, et al. Use of recombinant hirudin in patients with heparin-induced thrombocytopenia with thrombosis requiring cardiopulmonary, bypass. Anesthesiology 2000 92 263-6. 

Thrombotic thrombocytopenic purpura is a rare acute or subacute disease in adults, rather similar to the hemolytic uremic syndrome in children, in which there is systemic malaise, fever, skin purpura, renal failure, hematuria and proteinuria. Hemorrhagic infarcts caused by platelet microthrombi occur in many organs in the brain they may cause stroke-like episodes (Matijevic and Wu 2006) although more commonly there is global encephalopathy. The blood film shows thrombocytopenia, hemolytic anemia and fragmented red cells. The differential diagnosis includes infective endocarditis, idiopathic thrombocytopenia, heparin-induced thrombocytopenia with thrombosis, systemic lupus erythematosus, non-bacterial thrombotic endocarditis and disseminated intravascular coagulation. 

In the case of heparin-induced thrombocytopenia with thrombosis, all forms of heparin must be discontinued, including heparin flushes, and anticoagulation with argatroban or the recombinant hirudin lepirudin initiated.These agents should also be considered for the treatment of patients who have acute heparin-induced thrombocytopenia without thombosis because of the increased risk... 

Kramer R, Oberg-Higgins P, Russo L, Braxton JH. Heparin-induced thrombocytopenia with thrombosis syndrome managed with plasmapheresis. Interact Cardiovasc Thorac Surg 2009 8(4) 439-41. 

Heparin-induced thrombocytopenia (platelet count <150,000/ml or a 50% decrease from the pretreatment value) occurs in about 0.5% of medical patients 5 to 10 days after initiation of therapy with standard heparin. The incidence of thrombocytopenia is lower with low-molecular-weight heparin. Thrombotic complications that can be life threatening or lead to amputation occur in about one-half of the affected heparin-treated patients and may precede the onset of thrombocytopenia. The incidence of heparin-induced thrombocytopenia and thrombosis is higher in surgical patients. Venous thromboembolism occurs most commonly, but arterial thromboses causing limb ischemia, myocardial infarction, and stroke also occur. Bilateral adrenal hemorrhage, skin lesions at the site of subcutaneous heparin injection, and a variety of systemic reactions may accompany heparin-induced thrombocytopenia. The development of IgG antibodies against complexes of heparin with... 

Figure 24.4 The decision-analytic model shows the three strategies that were examined by Arnold and researchers [22] to evaluate the financial implications of the direct thrombin inhibitor argatroban for early treatment (<48 hours after thrombocytopenia onset), compared with delayed treatment, of heparin-induced thrombocytopenia (HIT) with or without thrombosis.

Heparin-induced thrombocytopenia Warfarin should be used with caution in patients with heparin-induced thrombocytopenia and deep venous thrombosis. 

Argatroban is a small molecule thrombin inhibitor that is FDA approved for use in patients with heparin-induced thrombocytopenia (HIT) with or without thrombosis and coronary angioplasty in patients with HIT. It, too, has a short half-life, is given by continuous intravenous infusion, and monitoring is done by aPTT. Its clearance is not affected by renal disease but is dependent on liver function. The drug requires dose reduction in patients with liver disease. Patients on argatroban will demonstrate elevated INRs because of test interference, rendering the transition to warfarin difficult. 

Lubenow N, Eichler R Lietz T, et al, Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia an analysis of three prospective studies, Blood 2004 104 3072-3077. 

The most devastating complication is heparin induced thrombocytopenia (HIT) (I). In contrast with other immune mediated thrombocytopenia, HIT is associated with thrombosis. 

For the past few decades, heparin has been widely used for the prevention of postoperative thiomboemboUsm (6,7). However, there are several adverse side-effects associated with the use of heparin such as bleeding, heparin induced thrombocytopenia, heparin induced thrombosis (8,9) and osteoporosis (10). In addition, the regimen of pioph actic heparin used in the prevention of deep venous thrombosis (DVT) is tedious, requiring 2 to 3 daily injections because of the limited bioavailability and short half-life of heparin when administered subcutaneously. 

Argatroban has been approved in the USA and Canada for the prophylaxis and treatment of thrombosis in patients with heparin-induced thrombocytopenia, and in Japan and Korea for various thrombotic disorders. Its effects can be monitored using the activated partial thromboplastin time for low doses and the activated clotting time for high doses. Its pharmacology, clinical pharmacology, and uses have been reviewed (7-14). 

A third variety, so-called delayed-onset heparin-induced thrombocytopenia has also been described in several reports. In 12 patients, recruited from secondary and tertiary care hospitals, thrombocytopenia and associated thrombosis occurred at a mean of 9.2 (range 5-19) days after the withdrawal of heparin nine received additional heparin, with further falls in platelet counts (32). In a retrospective case series, 14 patients, seen over a 3-year period, developed thromboembolic complications a median of 14 days after treatment with heparin (33). The emboli were venous (n — 10), or arterial (n — 2), or both (n — 2) of the 12 patients with venous embolism, 7 had pulmonary embolism. Platelet counts were mildly reduced in all but two patients at the time of the second presentation. On readmission, 11 patients received therapeutic heparin, which worsened their clinical condition and further reduced the platelet count. 

Venous limb gangrene due to heparin-induced thrombocytopenia is characterized by distal tissue losses, with extensive venous thrombosis involving large veins and small venules (53). This reaction seems to be related to acquired deficiency of protein C induced by concomitant oral anticoagulants. 

From the therapeutic point of view, prophylaxis of thrombosis must be continued after withdrawal of heparin, since even when there is no evidence of thrombosis in association with heparin-induced thrombocytopenia, thrombosis can follow after some days (52). Because of cross-reactivity, low molecular weight heparin should not be used when heparin has been withdrawn because of heparin-induced thrombocytopenia nor should warfarin be used, because of the risk of venous gangrene, at least until the thrombocytopenia has resolved. Patients with life-threatening or limb-threatening thrombosis can be treated with thrombolytic drugs. Current views are that two antithrombotic drugs should be used, for example danaparoid plus lepirudin (58). 

Two forms of heparin-induced thrombocytopenia (HIT) have been observed. The first (HIT I) is a transient, mild, and benign thrombocytopenia seen soon after initiation of heparin therapy (normally within 2 days) and is felt to be due to inherent plateletaggregating properties of heparin. A second, more severe form of HIT (HIT II) is typically seen later and is immune-mediated. The incidence of HIT II is estimated at 3-5%. The onset is generally 3-14 days after initiation of heparin therapy but may occur sooner with repeat exposure. HIT II may occur with any dose and type of heparin, but the frequency is highest with continuous intravenous infusions of unfractionated heparin. HIT with subsequent thrombosis is a feared complication. These thrombi can form in the venous or arterial circulation. Thrombotic complications include necrotic skin lesions, myocardial infarction, stroke, and gangrene. Hyperkalemia may be seen with heparin therapy due to aldosterone synthesis inhibition. 

Heparin-induced thrombocytopenia (HIT) frequently goes unrecognized and is associated with a high risk of thrombosis and mortality. HIT is diagnosed based on clinical and laboratory data. It requires aggressive treatment with a direct thrombin inhibitor. 

The second type of heparin-induced thrombocytopenia is severe and may be associated with a platelet count below 100,000/mm and thrombosis. ° ° The platelet count generally begins to decline 5 to 10 days after the start of heparin therapy (sooner in patients previously treated with heparin). Thrombocytopenia and thrombosis may develop with low-dose heparin, heparin-coated catheters, or even heparin flushes. Historically, the reaction was thought to be mediated by the formation of antibodies to the platelet-heparin complex. However, evidence suggests a complex interaction between heparin, platelet factor 4 (PF4), platelet membrane Fc receptors, and possibly heparin-like molecules on the surface of endothehal cells (Fig. 102-6). Circulating heparin reacts with PF4 to produce a... 

UFH can cause autoimmune heparin-induced thrombocytopenia. This rare but potentially lethal complication is associated with thrombosis and is treated by prompt withdrawal of UFH and initiation of alternative anticoagulation therapy. 

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